Human African trypanosomiasis (HAT) occurs in 36 nations of sub-Saharan Africa. In 2015 the World Health Organization (WHO) estimated 20,000 actual cases with 65 million people at risk. Transmitted by tsetse flies, the disease is due to a chronic infection of Trypanosoma brucei gambienese (in western and central Africa, over 98% of reported cases) or an acute infection of Trypanosoma brucei rhodesiense (in southern and eastern Africa). The T. b. gambiense infection is characterized by a slow progression from early (hemolymphatic) stage—where many patients are asymptomatic—to late stage disease, after the parasites have entered the central nervous system (CNS). The T. b. rhodesiense infection is characterized by earlier onset of symptoms and a more rapid progression from early to late stage. In either case, late stage HAT is always fatal if untreated (who.int/mediacentre/factsheets/fs259/en/).
The need for new anti-HAT drugs continues to persist, as current drugs are few, antiquated, toxic, prone to resistance, and require parenteral administration. Treatments for T. b. rhodesiense infections are limited to suramin (a polysulfonated naphthylurea) for early stage and melarsoprol (an organoarsenical) for late stage disease. Treatments for T. b. gambiense infections include pentamidine (an aromatic diamidine) for early stage and melarsoprol, eflornithine, or nitifurtimox-eflornithine combination therapy (NECT) for late stage disease (who.int/mediacentre/factsheets/fs259/en/; Astelbauer et al., Int. J. Antimicrob. Agents 38:118 (2011); Burri, Parasitology 137:1987 (2010)).
There is need for compounds that are orally available, cross the blood brain barrier, and are effective against trypanosomes and other neurological pathogens.